Prader-Willi syndrome (PWS) is a disease caused by mutations on human chromosome 15 leading to “floppy” infants initially, and obesity and sleep disorders later. Although genetic defects underlying PWS have been documented, it is still not well understood how the loss-of-function of genes results in various symptoms in PWS. It has been shown that the dysfunction of the hypothalamus, a brain structure, contributes to symptoms seen in PWS patients. Since the hypothalamus comprises many specific types of nerve cells (neurons) with distinct functions, it is essential to pinpoint changes in these neurons responsible for PWS. A specific group of nerve cells containing the neuropeptide melanin-concentrating hormone (MCH) promotes food intake and sleep in humans and animals. A dysfunctional hypocretin/orexin system has been found in diseases and conditions that exhibit abnormal sleep patterns as seen in PWS. In this application, we will examine the hypothesis that overactivation of MCH neurons is responsible for a dysfunctional hypocretin system and increased food intake in PWS. Since PWS is a complicated disease involving defects in many genes, it is essential to delineate the contribution of each defective gene to PWS symptoms. Animal models involving mutations of individual genes have provided additional insight into our understanding of PWS. By using a sophisticated approach to directly monitor activities in MCH neurons in live brain tissues from normal and PWS-like mice, we will study two factors determining the function of these neurons. First, we will discern the capability of MCH neurons to generate nerve impulses (action potentials), which triggers the release of MCH. Next, we will examine stimulatory inputs onto MCH neurons, which promote the induction of action potentials. We expect that these two functions would be up regulated in PWS mice, helping to explain the symptoms in PWS patients. We hope that our results will start a new avenue to understand the connections between genetic causes and diagnosed symptoms, and ultimately lead to the development of new treatments for PWS.